Fabiano Altieri
Design and rationalizing warhead for the PROTAC targeting gamma-tubulin using neural networks.
Rel. Jacek Adam Tuszynski, Maral Aminpour. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2022
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Abstract
PROTAC technology is a new unconventional way to target and destroy tumor cells, which exploits biological processes instead of inhibiting the function of a protein, as typical of conventional drugs. Essentially, PROTAC drugs are based on 3 parts: the warhead ligand which binds to the protein of interest (POI); the E3 ligand which binds to E3 ligase and a linker, which links covalently the warhead and the E3 ligand. Moreover, PROTAC drugs aim to accelerate the degradation rate of the POIs, since they have the goal of keeping POI and E3 ligase close together for as long as possible, thus they accelerate the ubiquitination process and, consequently, the degradation mediated by proteasome.
Rationalizing each part of the PROTAC is critical, but one of the great advantages is to use compounds that bind to any part of the protein and no longer just the active site, which by the way are affected by higher probability to mutate in tumor cells, effectively rendering that site untargetable
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